Project Summary/ Abstract: The major focus of epigenetic mechanistic studies to date has centered on the interplay between histone or DNA modifying proteins and transcription factors. These studies have yielded many fundamental insights into cancer biology and novel therapeutic targets, yet recent advances suggest that an additional critical level of control of the epigenome is conferred through the three dimensional (3D) structure of chromosomes. The Cancer Genome Dynamics Program (CGD) is a new scientific program, composed of 46 basic and clinical investigators from 13 departments at NYU School of Medicine and other NYU colleges. The goal of CGD is to investigate the connections between transcription, DNA sequence, chromatin status and 3D chromosome architecture to gain insight into how alterations at any level can initiate and/or promote tumor formation and progression. Led by Jane Skok, PhD and William Carroll MD, the program investigates the complex relationship between the linear and 3D genetic and epigenetic landscape of human tumors. Our crucial and overarching objective is to translate these discoveries into novel cancer prevention and treatment strategies. CGD research is organized into three complementary thematic aims: Aim 1: To determine fundamental mechanisms of genetic and epigenetic regulation and their dysregulation in cancer; Aim 2: To elucidate the role of DNA damage and repair in tumorigenesis and cancer progression; Aim 3: To discover the changes in chromosome architecture that activate oncogenic transcriptional programs. Since the last CCSG renewal in 2012, members have contributed 702 total publications, with 9.4% intra- programmatic (10% since program inception in 2016), 31% inter-programmatic and 30% inter-institutional (with NCI-CCs) publications. We have $11.4M ($3.5M NCI) in peer-reviewed funding ($14.3M total funding). CGD is a disease-oriented thematic program with direct translational and clinical impact. During the current funding period, CGD researchers have made new discoveries directly relevant to multiple types of cancer, including hematological malignancies (acute myeloid leukemia, acute lymphoblastic leukemia and multiple myeloma), breast cancer, prostate cancer, brain tumors and gynecological malignancies. Several of these discoveries have been, or are being, translated by clinician members of CGD into clinical trials at PCC. CGD researchers also address specific cancer burdens within our catchment area, including work on a non-coding RNA classifier in triple negative breast cancer and a protein classifier that can distinguish prostate cancer in African American males. Our work on DNA repair and mutagenesis is highly relevant to unusual carcinogens in the New York City environment. CGD has pioneered and introduced new technical, as well as bioinformatic, approaches that benefit all PCC members, and established the clinical sequencing platform at PCC that performs over 1,000 NGS tests/year.